morphine-chloride and Substance-Withdrawal-Syndrome

A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in position 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of the 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 were synthesized from oxymorphone (11), which was 3-O-benzylated, 6,14-bis-O-methylated with dimethyl sulfate, hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3, 4, 5, 7, 9, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous and oral administration. The most potent derivative in this series (15) showed a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analogue oxymorphone (11). The 14-OCH3 series also exhibited a considerably higher affinity to opioid receptors in binding studies using [3H]naloxone as ligand when compared to their 14-OH analogues.

Topics: Analgesia; Animals; Binding, Competitive; Biological Assay; Brain; Cell Membrane; Drug Evaluation, Preclinical; Humans; Indicators and Reagents; Mice; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Rabbits; Rats; Receptors, Opioid; Respiration; Structure-Activity Relationship; Substance Withdrawal Syndrome

A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.

Topics: Analgesics; Animals; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Haplorhini; Humans; Lethal Dose 50; Macaca mulatta; Molecular Conformation; Nalorphine; Narcotic Antagonists; Rabbits; Stereoisomerism; Structure-Activity Relationship; Substance Withdrawal Syndrome; Substance-Related Disorders; X-Ray Diffraction